Testosterone composition of matter and process



United States Patent ()fifice BfilBJdl Patented Apr. 11, 1967 3,313,701TESTUSTERONE COMPfiSlTION OF MATTER AND PROCESS John C. Babcock and JAllan Campbell, Kalamazoo, Mich, assignors to The Upjohn Company,Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Aug. 27,1963, Ser. No. 304,978 4 Claims. (Cl. 167-74) This application is acontinuation-in-part of application Ser. No. 114,621, filed June 5,1961.

This invention relates to therapeutic compositions containing7a,17a-dimethyltest0sterone and to a method for their use.

In the treatment of clinical conditions calling for an increase in thestorage of protein and the stimulation of tissue growth, theadministration of anabolic agents is frequently beset by concomitantandrogenic side effects in the agents employed. The development of malesexual characteristics in the course of anabolic therapy is a limitingfactor with agents heretofore available.

Comparative studies have shown that 7a,17a-dimethy1 testosterone (J. Am.Chem. Soc, 81:4069 [1959]) offers an unexpected split between anabolicand androgenic activities at therapeutically effective anabolic dosagelevels. With this agent it is possible to provide anabolic therapy whichis essentially free of undesirable androgenic side effects. This splitin activity provides a sharp departure from related compounds in theart. For example, the anabolic/androgenic ratio as obtained in rigidlycontrolled, double cross-over studies of anabolic activity in monkeysand androgenic activity in rats is 1.9 for 7a,17a-dimethyltestosteroneas compared with 1 for methyltestosterone, a commonly used standard. Inhumans, the anabolic potency is significantly greater than othercommonly used anabolic steroids.

A temporary and useful repression of breast tumors is observed ontherapy with this compound.

A daily oral dose of from about 0.25 to about 5 mg. per day of7a,17a-dimethyltestosterone has been found to provide highly effectiveanabolic therapy essentially free of undesirable androgenic sideeffects. The same regimen is appropriate for clinical utilization of theantitumor activity described. The exact dosage schedule, of course, mustbe determined individually according to the subjects age, weight,response to the medication and severity of the condition being treated.In general, however, a regimen of about 0.01 to about 0.03 mg./kg.bodyweight/day is preferred for children and about 0.02 to about 0.08mg./kg. bodyweight/day for adults.

In adapting the active ingredient for use in mammals, including humans,the novel compositions are suitably presented for administration in unitdosage form as tablets, pills, capsules, powders, Wafers, cachets,granules, oral dispersions, and the like.

For preparing solid compositions such as tablets, the active ingredientin crystalline, powdered, or micronized form is mixed with aconventional tableting component such as lactose, cornstarch, dicalciumphosphate, terra alba (calcium sulfate), talc, stearic acid, calciumstearate, 'gums, and functionally similar materials constitutingpharmaceutical diluents or carriers. The tablets or pills can belaminated or otherwise compounded to provide a dos-age form affordingthe advantage of prolonged or delayed action or of predeterminedsuccessive action of the enclosed medication. For example, the tablet orpill can comprise an inner dosage and outer dosage component, the latterbeing in the form of an envelope over the former. The two components canbe separated by an enteric layer which serves to resist disintegrationin the stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids or mixtures of polymeric acids with such materials asshellac, shellac and cetyl alcohol, cellulose acetate phthalate and thelike. A particularly advantageous sustained release coating comprises astyrene ma-leic acid copolymer.

The liquid forms in which the novel compositions of this invention canbe incorporated include aqueous solutions or suspensions, as well aselixirs and similar pharmaceutical vehicles. Suitable dispersing orsuspending agents for aqueous suspensions include the synthetic andnatural gums such as tragacanth, acacia, dextran, methylcellulose,polyvinylpyrrolidone, gelatin and the like.

The term unit dosage form as used in the specification and claims hereinrefers to physically discrete units suitable as unitary dosages forhuman subjects, each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical diluent, carrier orvehicle. The specification for the novel unit dosage forms of thisinvention are dictated by and directly dependent on (a) the uniquecharacteristics of the active material and the particular therapeuticeffect to be achieved and (b) the limitations inherent in the art ofcompounding such an active material for therapeutic use in humans, asdisclosed in detail in this specification, these being features of thepresent invention. Examples of suitable unit dosage forms, as heretoforedescribed, are tablets, capsules, pills, powder packets, wafers,cachets, granules, solutions or suspensions for oral use, suppositories,and segregated multiples of any of the foregoing, and other formsalluded to herein.

The following examples illustrate the best mode contemplated forcarrying out this invention, but these examples are not to be construedas limiting the scope thereof.

EXAMPLE 1TABLETS A batch of 10,000 compressed tablets, each containing 1mg. of 7a,17ct-dimethyltestosterone, is prepared from the followingingredients:

, Gm. 7a,17ot-dimethyltestosterone 10 Lactose 40 The finely powderedsteroid and lactose are thoroughly mixed and granulated withsyrup-starch paste. Starch and calcium stearate are used as lubricants,and the tablets are compressed in the usual manner.

Administration of these tablets is on a schedule of 1 tablet daily foradults to stimulate weight gain.

EXAMPLE 2TABLETS In the formulation of Example 1, 2.5 gm. or 50 gm. canbe substituted for the 10 gm. of 7a,17a-dimethyltestosterone to givetablets containing 0.25 mg. or 5 mg., respectively, which can beadministered on the same schedule for anabolic therapy.

EXAMPLE 3ORAL ANAB OLIC ACTIVITY This test was carried out using themethod of Stucki et al., Endocrinology 66:585 (1960). Young adult femalemonkeys were ovariectomized and acclimated to a balance ward of rigidlycontrolled environment. Each day the animals were oifered 200 ml. ofwater and an amount of constant composition diet sufficient to permitslow weight gain if no anabolic agent were administered. During controland drug periods alike, each animal was given twice a day one sugar cubesoaked in 0.6 ml. of a multiple vitamin preparation. Oral drugadministration was accomplished by instilling the requisite amount of analcohol solution of the test compound into the sugar cube several hoursbefore it was soaked with the vitamin suspension and given to theanimal.

All the animals were kept on balance continuously. Collection of faeces,urine and food remnants was made every other day at the time bodyweights were obtained. Homogenates of the collections were prepared andaliquots analyzed using a modified Kjeldahl procedure for total nitrogenand a flame photometer for potassium. Daily balance was calculated bycomparison of these values with those obtained from food analyses.

In all experiments either a spot single point assay or a quantitativetwin crossover assay design (Finney, Statistical Method in BiologicalAssay, 1952, p. 265; Hafner Publishing Co., New York) involving fourmonkeys or a double-twin crossover design involving eight monkeys wasemployed. In crossover experiments two doses of the standard,fiuoxymesterone (9a-fluoro-11/3,17,B-dihydroxy- 17u-methyl-4-androstene-3-one) and two doses of the test compound (basedon results in preliminary spot assays) were employed. Each drug periodwas 14 days in length. The first drug period was preceded by a 1014 daycontrol period and similar control periods separated the two drugperiods and followed the second drug period.

To determine the anabolic effect produced by a test compound, theaverage amount of nitrogen retained per day for the last eight treatment(preand post-drug control) days was calculated. The difference betweenpredrug control and treatment values (A pre) and the difference betweenpost-drug control and treatment values (A post) was then calculated foreach monkey. By the use of appropriate statistical methods for the twincrossover assay, potency of the test drug was then calculated andexpressed in terms of the standard (fluoxymesterone) for each parameterof nitrogen retention using A pre-, A postand on-drug values. Potassiumbalance data were similarly treated. Body weight gain during drugtreatment was also used to calculate drug potency.

The average of all seven estimates of potency was then determined. Bysuitable conversion, potency can also be expressed in terms of otherdrugs, for example, methyltestosterone. Results obtained withquantitative double twin cross-over assays on7a,17a-dimethyltestosterone and methyltestosterone are presented in thefollowing table:

TABLE.ANABOLIC POTENCIES OF 7a.17a-DIMETHYL- TESTOSTERONE ANDMETHYLTESTOSTERONE RELA- TIVE TO STANDARD DRUG, FLUOXYMESTERONE 4EXAMPLE 4ANDROGENIC ACTIVITY The procedure employed was that describedby Lyster et al., Endocrinology, 58: 781 (1956). The test animals wererats of the Upjohn-Sprague-Dawley colony which were castrated at 26 to27 days of age. Beginning on the day following castration and continuingfor 9 days, the animals were given orally a suspension of test compoundin cottonseed oil in predetermined dosage. On the day following the lastdosage the rats were sacrificed and the seminal vesicles (exclusive ofcoagulating gland and contained secretion) were weighed. Multiple pointparallel line assays with 5 or more rats per point were used forquantitative potency estimates. The average weights of the seminalvesicles for the animals in each dosage level were determined andcompared with results obtained using the standard, methyltestosterone.The androgenic activity of the test compound was expressed as a multipleof that of methyltestosterone. Results were as follows:

Androgenic activity X methyltestosterone 7a,17a-dimethyltestosterone 3EXAMPLE 5ANABOLIC THERAPY In clinical studies on over 200 humans,7a,17u-dimethyltestosterone has produced the benefits of anabolictherapy at clinically efiective doses of 0.25 to 5 mg. per day withoutsignificant signs of androgenicity (acne, voice change, hirsutism,etc.).

EXAMPLE 6-COMBINATION THERAPY Gm. 70c,17oc-diII1CthYlt8StOSt6I0n6 0.5Tetracycline phosphate complex 125 Starch, bolted 50 Calcium stearate 1Talc 1 The starch, talc and calcium stearate are thoroughly mixed andthe finely divided active ingredients incorporated into the mixture. Theresulting material is milled, screened and filled into telescopingcapsules by conventional methods. One capsule or more daily is given forcombined anabolic and antibacterial therapy.

For more comprehensive antibacterial therapy in con junction withanabolic therapy, from about 25 to about 250 mg. of novobiocin can beincluded in each capsule of the above formulation for similaradministration.

What is claimed is:

1. A therapeutic composition comprisingzin oral unit dosage form, fromabout 0.25 to about 5 mg. of 7a,17adimethyltestosterone, dispersed in apharmaceutical carner.

2. A therapeutic composition comprising: in oral unit dosage form, fromabout 0.25 to about 5 mg. of 70:,1701- dimethyltestosterone and fromabout to about 250 mg. of tetracycline, demethyltetracycline,oxytetracycline, or chlortetracycline, dispersed in a pharmaceuticalcarrier.

3. A method for inducing anabolic effects in mammals essentially free ofaccompanying androgenic eifects comprising: administering orally7a,17a-dimethyltestosterone in an amount sufiicient to induce anabolicetfects but essentially free of accompanying androgenic effects.

4. A method for inducing anabolic effects in humans essentially free ofaccompanying androgenic effects com- 3,313,701 5 6 prising:administering o rally from about 0.25 to about OTHER REFERENCES 5 dallyof 7"lh'dunethyltestostemne' Campbell et al., Journal of the AmericanChemical References Cited by the Examiner Society 4069-1075 (1951)UNITED STATES PATENTS 5 ALBERT T. MEYERS, Pruinary Examiner. 2,965,54112/1960 Byrnes 167-65 JULIAN LEVHT Exammer- 3,017,323 1/1962 Gordon16765 SAM ROSEN, LEROY B. RANDALL,

3,138,529 6/1964 Takesue 16765 Assistant Examiners.

3. A METHOD FOR INDUCING ANABOLIC EFFECTS IN MAMMALS ESSENTIALLY FREE OFACCOMPANYING ANDROGENIC EFFECTS COMPRISING: ADMINISTERING ORALLY7A,17A-DIMETHYLTESTOSTERONE IN AN AMOUNT SUFFICIENT TO INDUCE ANABOLICEFFECTS BUT ESSENTIALLY FREE OF ACCOMPANYING ANDROGENIC EFFECTS.